Philadelphia chromosome, also known as the Philadelphia translocation, is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML). It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t(9; 22)(q34; q11). The presence of this translocation is a highly sensitive test for CML, since 95% of CML patients have this abnormality. The remaining 5% of CML patients typically have either a cryptic translocation that is invisible on G-banded chromosome preparations, or a variant translocation involving another chromosome or chromosomes as well as the long arm of chromosomes 9 and 22. However, the mere presence of the Philadelphia (Ph) chromosome is not sufficiently specific to diagnose CML, since it is also found in 25-30% of adult acute lymphoblastic leukemia (ALL) cases (and in 2-10% in pediatric ALL cases).
Nevertheless, these diseases are clearly distinct. Acute lymphoblastic leukemia (ALL) is a form of leukemia in which malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone marrow, and by spreading (metastasizing) to other organs. ALL is most common in childhood and young adulthood with a peak incidence at 4-5 years of age, and another peak in old age. The overall cure rate in children is 85%, and about 50% of adults have long-term disease-free survival. ‘Acute’ refers to the undifferentiated, immature state of the circulating lymphocytes (“blasts”), and to the rapid progression of disease, which can be fatal in weeks to months if left untreated. Treatment for acute leukemia can include chemotherapy, steroids, radiation therapy, intensive combined treatments (including bone marrow or stem cell transplants), and growth factors.
Chronic myelogenous (or myeloid) leukemia (CML) on the other hand is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood; it is thus a myeloproliferative disease. CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding. Historically, it has been treated with chemotherapy, interferon and bone marrow transplantation, although targeted therapies are now also available and used as standard of care.
The swapping of parts of chromosomes 9 and 22 observed in the Philadelphia chromosome gives rise to a BCR-ABL fusion gene (Melo, 1996). That is to say, part of the BCR (“breakpoint cluster region”) gene from chromosome 22 (region q11) is fused with part of the ABL gene on chromosome 9 (region q34). Abl stands for “Abelson”, the name of a leukemia virus which carries a similar protein. Two kinds of BCR-ABL transcripts (which yield p185 and p210 isoforms, named after their apparent molecular weight in kDa) are generated due to the breakpoint of the BCR region. The fused “BCR-ABL” gene is located on the resulting, shorter chromosome 22. ABL carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), and the BCR-ABL fusion gene product is also a tyrosine kinase (Faderl et al., 1999).
The fused BCR-ABL protein interacts with the interleukin-3 β common receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities, and potentially promoting progression of CML from chronic phase towards untreatable blast crisis. The tyrosine kinase action of the BCR-ABL protein is believed to be the pathophysiologic cause of chronic myelogenous leukemia. Targeted therapies specifically inhibiting the activity of the BCR-ABL protein have been developed. The first of these was imatinib (marketed as its mesylate salt under the trade name Glivec® or Gleevec®). These and other tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of BCR-ABL in CML (Hehlmann et al., 2007). Limited success was also reported when treating Philadelphia chromosome positive (Ph+) ALL with BCR-ABL inhibitors (Yanada and Naoe, 2006; Piccaluga et al., 2006).
Despite the fact that introduction of imatinib and second-generation BCR/ABL inhibitors (e.g. dasatinib) has revolutionized treatment of patients with Philadelphia chromosome positive (Ph+) leukemias, it is a known problem that leukemia cells persist even in successfully treated patients, and some patients develop resistance and ultimately relapse (Swords et al., 2007; Buchert, 2007; Li and Li, 2007; Kujawski and Talpaz, 2007). The reasons for these drawbacks are not entirely resolved.
Thus, it would be advantageous to have further options to treat patients with Philadelphia chromosome positive leukemia, particularly those patients not responsive to treatment with BCR-ABL inhibitors.